Eyeblink conditioning in rabbits will be used as a "model behavioral system" in the analysis of the neural substrates of learning. The medial septum, CA1 hippocampus and prefrontal cortex, important substrates for a variety of learning tasks in both humans and other mammals, will be studied. The "trace" eyeblink conditioning task, in which the rabbit must form a short-term memory trace that the tone conditioned stimulus has occurred in order to appropriately control the blink and avoid an airpuff to the eye, will be used. This task depends upon hippocampus for its successful acquisition. Single neuron activity will be recorded in three interconnected stations of the hippocampal system-from medial septum (the principal source of cholinergic drive to the hippocampus proper), from the CA1 subfield of the hippocampus (the major output of the hippocampal trisynaptic circuit), and from medial prefrontal cortex (which receives afferent drive from CA1 both directly, and indirectly via dorsomedial thalamus). The short term memory load will be manipulated by increasing the trace interval to determine if this affects neuronal processing in any of the regions. The relationships between changes in neuronal firing activity and behavioral acquisition will be examined to determine if they occur at specific time point in training or with specific latencies relative to the response within each region. The excitability changes recorded in vivo will be directly correlated with biophysical measurements of cellular substrates for the excitability increases made in vitro in hippocampal and neocortical slices. Rabbits will be trained to different stages on their "neuronal acquisition curves" and the degree of the slow calcium-mediated after hyperpolarization reduction in CA1 pyramidal neurons will be compared in vitro at different stages of training. Comparable measures will be made after training in cortical slices. The septal cholinergic system will be closely examined to determine if this system may play a particularly important role in establishing the postsynaptic excitability changes recorded both in vivo and in vitro from CA1 pyramidal neurons during training. Evidence for spatial concentrations of change will be sought to determine if neurons in each station function homogeneously during and after acquisition of a hippocampally-dependent task and to see if their function changes as the memory load of the task is increased. The proposed studies are relevant to a better understanding of how the hippocampus and a neocortical region to which it projects function during learning in all mammals, including humans. The hippocampus becomes dysfunctional in Alzheimer's disease and often in aging, leading to memory loss. Its dysfunction is also thought to underly some of the cognitive manifestations of schizophrenia. Frontal cortex is especially likely to be traumatized in auto accidents. Prefrontal damages causes disorders of attention, recent memory, initiative and affect. Understanding hippocampal and prefrontal cortical cellular activity during learning in normal brain will facilitate developing pharmacologic and other clinical strategies for treating their functional disruptions.